Abstract Introduction: IGSF8 (Immunoglobulin superfamily member 8) is a novel immune checkpoint that regulates both natural killer (NK) cell cytotoxicity and dendritic cell (DC) -mediated antigen presentation. GV20-0251, an artificial intelligence-designed antibody targeting IGSF8, is being evaluated in a Phase 1/2a clinical trial (NCT05669430) for metastatic solid tumors. Here, we report pharmacodynamic evaluation and potential predictive biomarkers from the monotherapy dose-escalation cohort. Methods: Target engagement and modulation were measured by flow cytometry on circulating CD3+ T cells. Pre- and on-treatment tumor tissues were assessed for IGSF8 expression and immune regulation by immunohistochemistry (IHC) and RNA-seq. IGSF8 expression in human tumors was examined using RNA-seq data from The Cancer Genome Atlas (TCGA) and IHC on tumor microarrays. Clinical response was evaluated per RECIST v1. 1. Results: Forty-two participants were enrolled in this first-in-human monotherapy dose-escalation study. Among 16 evaluable cutaneous melanoma patients who had relapsed following prior anti-PD-1 treatment, three confirmed partial responses were observed. Target occupancy analysis demonstrated saturated IGSF8 binding by GV20-0251 on circulating T cells at doses ≥3 mg/kg. Treatment resulted in rapid reduction of IGSF8 cell surface expression on both circulating T cells and malignant cells within tumor tissues. IHC analysis of five paired tumor biopsies showed increased intratumoral infiltration of CD56+ NK cells and CD8+ T cells following treatment. RNA-seq of four paired melanoma tissues revealed immune cell infiltration, antigen presentation, and NK cytotoxicity as the top upregulated pathways post-treatment. Analysis of pretreatment tumors (n=10) revealed that patients achieving clinical benefit (partial response or stable disease) had higher IGSF8 RNA and membrane protein expression. In contrast, no objective response was observed in tumors with low or absent IGSF8 expression. TCGA database analysis demonstrated significant IGSF8 upregulation across multiple tumor types, including melanoma, hepatocellular carcinoma, and lung cancer. IHC examination of tissue microarrays further confirmed high IGSF8 positivity in these tumor types, all of which present high unmet medical needs. Conclusion: Pharmacodynamic analyses confirmed complete target occupancy at pharmacologically active doses with robust target modulation, leading to enhanced antigen presentation coupled with NK and CD8+ T cell infiltration. Preliminary data suggest a relationship between IGSF8 expression on cancer cells and clinical benefit, warranting further investigation. Collectively, these results provide proof-of-mechanism for GV20-0251 as a novel cancer immunotherapy and establish a potential biomarker strategy for further clinical development. Citation Format: Xingfeng Bao, Caibin Sheng, Inderjit Mehmi, Julio A. Peguero, Shivaani Kummar, Patricia LoRusso, Janice M. Mehnert, Aung Naing, Alexander I. Spira, Justin F. Gainor, Omid Hamid, Justin T. Moyers, Jin Wang, Xihao Wu, Hong Xiao, X. Shirley Liu, Tengfei Xiao, Kristopher Wentzel. Evaluation of pharmacodynamic and potential predictive biomarkers for GV20-0251, an anti-IGSF8 antibody, as monotherapy from ongoing Phase 1/2a study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT001.
Bao et al. (2026) studied this question.